Natural killer (NK) cells comprise an arm of the immune system that specifically target virus-infected host cells. NK cells have recently been demonstrated in mouse and humans to possess novel features including the ability to generate immune memory following viral infection. NK cell-deficiency in humans results in severe health complications due to susceptibility to a variety of viral infections. Our long-term goals are to understand the general biology of NK cells and the molecular basis by which these powerful effector cells can mediate protection against pathogen invasion. Mouse cytomegalovirus (MCMV) infection is a well-characterized system for the study of anti- viral NK cell responses. The pathogenesis of MCMV and immune evasion strategies employed by this virus closely mimic features of human cytomegalovirus (HCMV), thus providing a good model for HCMV infection, which causes life-threatening disease in newborns and immunocompromised individuals. Together with the abundance of cutting- edge immunological tools and reagents available only in mice, MCMV infection presents a powerful model for identifying the molecular requirements that control activation and inhibition of NK cells responses. Using this model, our preliminary studies indicate that pro-inflammatory cytokines such as IL-12 play an important role in the generation of NK cell memory following MCMV infection. The overall goals of this proposal are to understand the influence of opposing pro- and anti-inflammatory cytokine signaling pathways on the response of NK cells against viral infection. Aims 1 and 2 will build upon our preliminary findings and investigate the role of pro-inflammatory and regulatory cytokines, and downstream signaling components, on the generation of effector and memory NK cells following MCMV infection. Using newly-engineered transgenic mouse models, Aim 3 will address how inflammation-induced transcription factors direct NK cell function in a cell-intrinsic manner during MCMV infection. Together, the studies in this proposal will not only increase our understanding of the general molecular mechanisms whereby NK cells contribute to host defense during viral infection, but also establish novel clinical paradigms for how the NK cell compartment may be harnessed for immunization strategies against infectious disease. PUBLIC HEALTH RELEVANCE: Cytomegalovirus (CMV) can cause serious health problems and life-threatening disease in newborns and immune-suppressed individuals (including cancer and transplant patients). Using a mouse model of CMV, this proposal seeks to understand the role of opposing inflammatory cytokines and transcription factors in the natural killer (NK) cell- mediated control of viral infection. Defining the molecular mechanisms by which NK cells respond to CMV infection will potentially lead to therapeutic benefits.